Disease-Modifying Genes in Huntington's Disease: HD is a devastating neurodegenerative disorder with a long, costly, debilitating course to premature death, ~15 yrs after clinical diagnosis. There is a dire need for effective therapies to alleviate the suffering and cost to the individual, family and society. The HD mutation in HTT is an expanded CAG trinucleotide repeat whose length is the main factor determining the timing of clinical onset. Although it is often assumed that the length of polyglutamine in huntingtin drives the rate of pathogenesis leading to HD onset, our data from HD subjects do not support this conclusion. Disease-associated HTT alleles with the same pure CAG repeat size may produce different-sized polyglutamine tracts due to variable glutamine-encoding CAA codons, with no commensurate hastening in HD onset due to extra glutamines. Rather, age-at-onset is best explained by a property of the pure CAG repeat separate from its coding potential. We have discovered that HD age-at-onset is modified by genetic variation at 6 loci that encode genes involved in a variety of DNA maintenance processes. These genetic modifiers, in both humans and mouse models, implicate somatic expansion of the CAG repeat rather than encoded polyglutamine as the factor determining age-at-onset. By contrast, symptomatic progression shows at best a weak correlation with CAG repeat size, while duration of manifest disease (i.e., the time from motor diagnosis to death) is independent of CAG repeat length, suggesting that other factors are paramount in determining pathogenesis from onset to death. Overall our findings point to HD as comprising two distinct components: 1) length-dependent somatic expansion of the CAG repeat up to and above a threshold length (rate driver) that then engages toxicity and 2) as yet uncertain mechanism(s) by which the somatically expanded repeat triggers damage when the threshold length is reached (toxicity driver). The nature of the toxicity driver(s) is not yet unequivocal. An effect on huntingtin by above-threshold polyglutamine (rather than continuous length-dependent toxicity) is both attractive and consistent with the effects of long CAG repeats in model systems, but other mechanisms that act at the transcriptional or RNA level have also been suggested as causative. The success of our human genetic strategy has begun to provide new targets for therapeutic interventions to delay or prevent HD onset. In this renewal, we will identify additional rate modifiers to more fully delineate the process of somatic CAG expansion in humans and will extend our strategy to discover modifiers of manifest disease that implicate the nature of the toxicity driver or its damaging consequences. The identification of novel targets, implicated by the natural variation in biological processes ongoing in HD subjects themselves, will provide a firm foundation for developing pharmaceutical interventions that push those processes even farther, toward a strong therapeutic benefit. Thus, the promise of this grant is a new and powerful route to fulfilling the greatest need of both premanifest and manifest HD subjects and their families: effective treatments to block or delay onset and progression of the disease.